Simple sugar delays neurodegeneration caused by enzyme deficiency

June 20, 2018, Baylor College of Medicine
Dr. Marco Sardiello. Credit: Baylor College of Medicine

A new therapeutic approach may one day delay neurodegeneration typical of a disease called mucopolysaccharidoses IIIB (MPS IIIB). Neurodegeneration in this condition results from the abnormal accumulation of essential cellular molecules called mucopolysaccharides. Looking to find alternative therapeutic strategies for this rare genetic disease, a team of researchers investigated whether enhancing the cells' ability to clear accumulation of cellular waste would help eliminate the abnormal storage of mucopolysaccharides. They report in the journal Autophagy that the sugar trehalose increases cellular waste disposal and improves the neurological symptoms in a mouse model of the disease.

"MPS IIIB is one of about 50 characterized by the accumulation of material inside tiny cellular sacs called lysosomes," said corresponding author Dr. Marco Sardiello, assistant professor of molecular and human genetics and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine. "In the case of MPS IIIB, a mutation on a gene that codes for a lysosomal enzyme that breaks down a cellular material called , renders the enzyme ineffective. Consequently, the lysosome cannot do its work of degrading heparan sulfate to either discard it or recycle it, and the material accumulates."

Over the years, accumulation of heparan sulfate in lysosomes leads to degeneration of brain tissue. Although infants appear healthy at first, they slowly begin to show behavioral problems, hyperactivity, aggressiveness, sleep disturbances and loss of vision and hearing. Later in life, they become immobile and develop swallowing difficulties. Usually, they don't live past the second decade. Current strategies being tested for the treatment of this condition in animal models include attempting to correct the enzyme deficiency by providing a fully working enzyme. However, this approach faces challenges such as having limited ability to cross the blood-brain barrier and reaching the brain areas where the enzyme is needed.

A non-traditional approach

"We explored a way to treat this condition with a nontraditional approach," Sardiello said. "We recently discovered that the small sugar promotes the recycling of cellular waste. This made us think of an indirect approach to try to solve the accumulation of heparan sulfate. Instead of correcting the , we would try to overcome it by enhancing the cells' natural ability to discard cellular waste."

The researchers tested their approach on a mouse model of MPS IIIB. These mice have a mutation that results in the recapitulation of most of the clinical symptoms observed in patients, including progressive neurodegeneration, loss of vision, brain inflammation and shorter lifespan.

One group of MPS IIIB mice received trehalose in the drinking water, while another group of MPS IIIB mice did not receive the sugar. As controls, normal mice without the mutation were provided water with or without trehalose. The researchers observed the animals for 11 months, taking samples at the middle and at the end of the observation period.

"The results were highly encouraging," said first author Dr. Parisa Lotfi, postdoctoral associate in the Sardiello lab. "The MPS IIIB mice treated with trehalose lived longer, improved their hyperactive behavior and delayed several neuropathological features, most notably the , when compared with MPS IIIB mice not treated with trehalose."

In addition, the researchers explored the molecular mechanism underlying the trehalose effect.

"Previously, we had discovered that trehalose activates TFEB, a master regulator of the lysosomal system. As the activity of TFEB increases, the degradation and clearance of molecules in the lysosomes becomes more efficient," said Lotfi. "Here, we were the first to quantify the amount of trehalose that crosses the blood-brain barrier and activates TFEB in the brain. In turn, TFEB activated the lysosomal system, which led to enhanced clearance of material accumulation, reduced neuroinflammation, retinal degeneration and vision loss and extended lifespan."

This study is the first to show that trehalose is acting through TFEB but no other molecules. Also, this is the first preclinical study showing that it is possible to delay retinal degeneration and loss of vision in a of MPS IIIB.

"The effect on the retina is important," Lotfi said. "Loss of vision is one of the most devastating aspects of some lysosomal diseases. In animal models, treatments based on enzyme replacement therapy do not reach the brain and do not counteract loss of vision. We think that in the future our strategy can potentially be used either as the main therapy or complementary to other therapies."

"Our results encourage us to consider that trehalose also may be effective in other lysosomal storage diseases, such as Batten disease," Sardiello said. "Trehalose is a widely used food additive with no current restrictions for human use."

Explore further: Research reveals strategy to potentially treat juvenile Batten disease

More information: Parisa Lotfi et al, Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency, Autophagy (2018). DOI: 10.1080/15548627.2018.1474313

Related Stories

Research reveals strategy to potentially treat juvenile Batten disease

February 6, 2017
Researchers at Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and King's College London have discovered a treatment that improves the neurological symptoms in a ...

Study holds hope of a treatment for deadly genetic disease, MPS IIIB

September 29, 2014
MPS IIIB is a devastating and currently untreatable disease that causes progressive damage to the brain, leading to profound intellectual disability, dementia and death—often before reaching adulthood.

Type of sugar may treat atherosclerosis, mouse study shows

June 7, 2017
Researchers have long sought ways to harness the body's immune system to treat disease, especially cancer. Now, scientists have found that the immune system may be triggered to treat atherosclerosis and possibly other metabolic ...

Biochemists confirm existence of theoretical genetic disorder

January 8, 2018
Thanks to the sequencing of the human genome, scientists can now discover potential disorders for which there are no known patients. One such disorder is MPS III-E, originally also called Dierks's disorder after its discoverer. ...

Photoreceptor cell death leads to blindness in CLN5 form of Neuronal Ceroid Lipofuscinosis

May 16, 2017
Researchers from the University of Eastern Finland have discovered a likely cause for visual impairment and eventual loss of vision in the Finnish variant of Neuronal Ceroid Lipofuscinosis (NCL). Visual impairment associated ...

Recommended for you

Zombie cells found in brains of mice prior to cognitive loss

September 19, 2018
Zombie cells are the ones that can't die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. And with a new letter in Nature, ...

Synthetic sandalwood found to prolong human hair growth

September 19, 2018
A team of researchers led by Ralf Paus of the University of Manchester has found that applying sandalwood to the scalp can prolong human hair growth. In their paper published in the journal Nature Communications, the group ...

Why some human genes are more popular with researchers than others

September 18, 2018
Historical bias is a key reason why biomedical researchers continue to study the same 10 percent of all human genes while ignoring many genes known to play roles in disease, according to a study publishing September 18 in ...

Separated entry and exit doors for calcium keep energy production smooth in the powerhouses of heart cells

September 18, 2018
Stress demands the heart to work harder and faster. To keep pace, the muscle must make its fuel at an accelerated rate. Bursts of calcium entering mitochondria—the cell's powerhouses—normally help control energy output, ...

Class of neurological disorders share 3-D genome folding pattern, study finds

September 18, 2018
In a class of roughly 30 neurological disorders that includes ALS, Huntington's Disease and Fragile X Syndrome, the relevant mutant gene features sections of repeating base pair sequences known as short tandem repeats, or ...

First gut bacteria may have lasting effect on ability to fight chronic diseases

September 18, 2018
New research showing that the first bacteria introduced into the gut have a lasting impact may one day allow science to adjust microbiomes—the one-of-a-kind microbial communities that live in our gastrointestinal tracts—to ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.